Vitamin C -or ascorbic acid- is important for several physiological functions, along with other factors, in the antioxidant protection of cells. Ascorbic acid represents the major water-soluble antioxidant in plasma and tissues. As such, it supports the recycling of antioxidants, the bioavailability of non-haeme iron, and the maintenance of several enzymatic functions.
The best characterized metabolic role of ascorbic acid is in the synthesis of collagen proteins but it also has important roles in the metabolism of neurotransmitters, steroids, drugs, and lipids. In addition it affects biosynthesis of some hormones, metabolism of the amino acid tyrosine and ascorbic acid is also a cofactor in the synthesis of carnitine, which is required for the transport of fatty acids into mitochondria for oxidation to provide energy for the cell.
Ascorbic acid is thought to be involved in reactions of drug and steroid metabolism. For example, Vitamin C deficiency significantly increases in the duration of action of the sleeping drug phenobarbital and other studies have clearly demonstrated positive correlations between ascorbic acid status and drug metabolism. It is thought that low ascorbic acid levels are responsible for the reduced synthesis of corticosteroids which accounts for the diminished responses to stress seen in vitamin C deficiency.
Nearly all tissues accumulate vitamin C, but levels are decreased by virtually all forms of stress. The concentration of ascorbic acid in the adrenals is very high; approximately one-third of the vitamin is concentrated in those glands, from which it is released with newly synthesized corticosteroids in response to stress. The ascorbic acid concentration of brain tissue also tends to be high and brain levels are among the last to be affected by dietary deprivation of vitamin C. A relatively large amount of ascorbic acid is also found in the eye, where it is thought to protect critical groups of proteins from oxidation.
There is no stable reserve of vitamin C; excesses are quickly excreted. Vitamin C status may be biased by genetic factors and certain individuals have a higher risk of deficiency. Vitamin C deficiency can be caused by low dietary intakes, as well as by conditions in which the metabolic demands for ascorbic are excessive, thus increasing the turnover of the vitamin in the body. Such conditions include smoking, environmental/physical stress, chronic disease, and diabetes. Indeed, children exposed to environmental tobacco smoke show reduced plasma ascorbic acid concentrations.
Vitamin C deficiency is classically presented as scurvy which becomes apparent in human adults after 45–80 days of stopping vitamin C consumption. Defects in collagen formation are manifested as impaired wound healing; oedema; haemorrhage in the skin, mucous membranes, internal organs, and muscles; and weakening of collagenous structures in bone, cartilage, teeth, and connective tissues along with swollen, bleeding gums and tooth loss. They also show lethargy, fatigue, rheumatic pains in the legs, muscular atrophy, skin lesions, massive sheet hematomas in the thighs and haemorrhages in many organs, including the intestines and eyes. These features are frequently accompanied by psychological changes: hysteria, hypochondria, and depression.
Marginal vitamin status is characterized by oxidative effects in certain tissues, for example, loss of reduced glutathione in lymphocytes, and loss of α-tocopherol with accumulation of lipid peroxidation products in retinal tissues. In addition, elderly people typically show total body vitamin C pools of reduced size, perhaps owing to reduced enteric absorption and increased turnover. In humans, marginal vitamin C status characterized by low plasma vitamin C levels and a depleted total body vitamin C pool which results in several non-specific pre-scorbutic signs and symptoms: lassitude, fatigue, anorexia, muscular weakness, and increased susceptibility to infection.
Sources of Vitamin C
Vitamin C is widely distributed in both plants and animals; however levels tend to vary with food storage time, due to the time-dependent oxidation of ascorbic acid. Fruits, vegetables, and organ meats (e.g., liver and kidney) are generally the best sources; only small amounts are found in muscle meats. Plants synthesize ascorbic acid, but most seeds do not contain it, and only start to synthesize it on sprouting. Some plants accumulate high levels of the vitamin (e.g., fresh tea leaves, some berries, guava, rose hips). Ascorbic acid-containing tissues of cruciferous vegetables of the family Brassicaceae typically contain compounds called glucosinolates, which when food is cut and cooked, degrade to products that react spontaneously with ascorbic acid to form complexes without vitamin C activity.
Substantial losses of vitamin C can occur during storage and are enhanced greatly during cooking. For example, after harvest, stored potatoes lose 50% of their vitamin C within 5 months, and 65% within 8 months. Apples and cabbage stored for winter can lose 50% and 40%, respectively, of their original vitamin C content. Losses in cooking are usually greater with such methods as boiling, for example, potatoes can lose 40% of their vitamin C content by boiling. Alternatively, quick heating methods can protect food vitamin C.
FUNCTIONS OF VITAMIN C
Ascorbic acid has been found to affect immune function in several ways. It has been shown to modulate T cell expression (a type of white blood cell that plays a central role in immunity) and immune function. It can stimulate the production of interferons, the proteins that protect cells against viral attack. It can stimulate the positive responses of neutrophils-another type of white blood cell involved in immune function-that attack invaders by releasing free radicals and protect these cells against free radical-mediated oxidative burst they produce. It can stimulate the synthesis of antibodies of the IgG and IgM classe that bind many kinds of viruses, bacteria and fungi to protect the body from infection. Studies have found that vitamin C increases the responses of white blood cells to proliferate upon infection, is associated with enhanced natural killer cell activity and decreases viral replication in cell culture systems.
Large doses of vitamin C have been advocated for prevention and treatment of the common cold, a use that was first proposed some 25 years ago by the Nobel laureate Dr Linus Pauling. Since that time, many controlled clinical studies have been conducted to test that hypothesis. A recent analysis of 29 randomized controlled trials noted a consistent benefit of vitamin C supplementation at around 200 mg/day in reductions of cold duration by 8% in adults and 13.5% in children. That analysis also showed that six trials including a total of 642 athletes and soldiers showed a 50% reduction in risk of developing a cold (1).
Infections other than colds
Ten of 14 randomized controlled trials found apparent reductions in incidence of hepatitis, pneumonia, bronchitis and pharyngitis/laryngitis/tonsillitis and 8 of 10 found apparent reductions in severity of infections and beneficial outcomes in terms of reduced number of days healing in Herpes labia, decreased symptom scores in bronchitis and reduction in severity of hepatitis (2-6).
Randomized trials have shown that vitamin C supplementation can protect against the progression of gastric symptoms known as gastric atrophy which appears to be related to reduced risk of gastric cancer, for which H. pylori is a risk factor (7,8).
A large, cross-sectional study indicated that plasma ascorbic acid was negatively associated with biomarkers of inflammation and endothelial dysfunction (endothelial dysfunction is an imbalance between the response to naturally circulating molecules that either relax or contract the inner lining of blood vessels and are associated with activities such as coagulation and immune function), suggesting that the vitamin has anti-inflammatory effects associated with reduced levels of endothelial dysfunction (9).
It is also thought that ascorbic acid may enhance the synthesis of the anti-inflammatory compounds of the prostaglandin E series, members of which the mediate the body’s response to histamine a compound involved in inflammation, so initiating an natural antihistamine effect. Circulating histamine concentration is known to be reduced by high doses of vitamin C, a fact that has been the basis of the therapeutic use of the vitamin to protect against histamine-induced anaphylactic shock. Further, blood histamine concentrations are elevated in several complications of pregnancy that are associated with marginal ascorbic acid status: pre-eclampsia (a disorder of pregnancy characterised by high blood pressure and large amounts of protein in the urine), and prematurity. Because blood histamine and ascorbic acid concentrations were negatively correlated in women in preterm labour, it has been suggested that the combined effects of marginal vitamin C status may result in the marked elevations of blood histamine levels seen in those conditions (10).
The antioxidant characteristics of ascorbic acid allow it to reduce the oxidation of low-density lipoproteins (LDLs), a key early event leading to atherosclerosis (a condition where the artery walls thicken as a result of invasion and accumulation of white blood cells). Being rich in both cholesterol and polyunsaturated fatty acids (PUFAs), LDLs are susceptible to lipid peroxidation by the oxidative attack of reactive oxygen species. Research has shown that oxidisation of LDLs is found in the early stages of atherosclerosis. According to this view, atherosclerosis can be reduced by protecting LDLs from free-radical attack. The full protection of LDLs appears to involve both ascorbic acid and vitamin E, the latter being important in quenching radicals produced within the interior environment of the LDL particle (11).
Subjects in the first National Health and Nutrition Examination Survey (NHANES I) with the highest vitamin C intakes showed 34% less cardiovascular death than subjects with lower estimated vitamin C intakes. Plasma ascorbic acid concentration was found to be highly negatively correlated with the values of several cardiovascular risk factors, including blood pressure, total serum cholesterol, and LDL cholesterol (12).
Resting blood pressure in humans has been found to be inversely related to vitamin C intake or plasma ascorbic acid concentration, and an intervention trial found vitamin C supplementation to reduce blood pressure and improve arterial stiffness in patients with non-insulin-dependent diabetes. The importance of hypertension as a risk factor for cerebrovascular and coronary heart diseases makes prospective blood pressure-lowering effects of vitamin C supplementation of considerable interest (13).
Risk of stroke has been found to be inversely related to vitamin C status. Elevated serum vitamin C concentrations were associated with reduced risk of cerebral infarction and haemorrhagic stroke in two large prospective studies in Japan and Finland. These effects, however, were not associated with the use of vitamin C supplements, suggesting a role for the consumption of vitamin C-containing fruits and vegetables (14,15).
High vitamin C intakes have been found to be associated with reduced risk of non-fatal ischemic heart disease, and clinical trials have found vitamin C supplementation to enhance the protective effect of aspirin in reducing risk of ischemic stroke, and to retard progression of atherosclerosis in patients with high cholesterol levels. A recent analysis of nine prospective trials concluded that high-level vitamin C supplements reduced the incidence of major coronary heart disease.
Vigorous physical activity increases ventilation rates and produces oxidative stress, which is thought to affect the function of the cells lining blood vessels (endothelial cells). Studies have shown that antioxidant supplementation can alleviate muscle damage and protein oxidation induced by exercise. That vitamin C may be especially important in such protection is indicated by the finding that vitamin C prevented acute endothelial dysfunction induced by exercise in patients with intermittent claudication (calf pain during walking) (16). This effect is likely due to the protection of nitric oxide, which relaxes blood vessels (endothelium-dependent vasodilation).
Metabolically produced reactive oxygen species (ROS) also appear to have essential functions as signaling molecules for the adaption of skeletal muscle to accommodate the stresses presented by exercise training or periods of disuse. Studies have shown that the responses of this system can be impaired by high-level antioxidant treatment. This finding raises questions as to what level of “peroxide tone” may be beneficial.
Diabetic patients and subjects with metabolic syndrome (characterised by the early stages of insulin resistance, high blood pressure and obesity) typically show lower serum concentrations of ascorbic acid than non-diabetic controls. Accordingly, reduced serum antioxidant activity has been implicated in the progression of the disease. Controlled intervention trials have shown that vitamin C supplementation can be effective in reducing markers of diabetes (erythrocyte sorbitol accumulation and urinary albumin excretion) in non-insulin-dependent diabetics. Treatment with vitamin C has also been shown to prevent changes in arterial blood vessels induced by levels of high circulating glucose (17,18).
Plasma ascorbic acid concentrations have been shown to be positively associated with memory performance in patients with dementia, and cognitive performance in older subjects. It has been suggested these conditions may increase the oxidation of ascorbic acid, an estimated 2% of which turns over in the brain each hour. It is also possible that vitamin C supplementation may enhance protection from the effects of inflammatory mediators and free radicals involved in the progression of neurodegenerative disease (19,20).
Low vitamin C status has been shown to be associated with increased risks of gestational diabetes and of premature delivery due to premature rupture of chorioamniotic membranes. The latter responded to vitamin C supplementation (21).
Ascorbic acid is critical for the health of the skin (epidermis), by virtue of its essential role in collagen synthesis. It is well documented that vitamin C-deficiency results in prolonged wound healing times. This is thought to involve their diminished rates of collagen synthesis, as well as their increased susceptibility to infections. Rapid utilization of the vitamin occurs where relatively high levels of ascorbic acid accumulate at wound sites.104 Greater concentrations of ascorbic acid appear to be required for the maintenance of wound integrity than for collagen development. Topical application of ascorbic acid has been found useful in treating photo-damaged skin, as well as inflammatory conditions of the skin such as acne and eczema. That wound repair typically decreases with aging has been suggested as indicative of increasing needs for vitamin C by older individuals.
Cataracts are thought to result from the cumulative photo-oxidative effects of ultraviolet light from which the lens is protected by three antioxidants: ascorbic acid, tocopherol, and reduced glutathione. The lens typically contains relatively high concentrations of ascorbic acid (e.g., as much as 30-fold those of plasma), which are lower in aged and cataractous lens. 105 Epidemiological studies have shown inverse associations of ascorbic acid status and cataract incidence, however, an 8-year randomized trial with more than 11,500 subjects found intervention with both ascorbic acid (500 mg/day) and vitamin E (400 IU/day) to have no effect on cataract risk.
Its redox properties give ascorbic acid an important role in the antioxidant protection of the lung which is consistently exposed to high concentrations of oxygen and inhaled toxic gases. Patients with asthma or acute respiratory distress syndrome typically show lower than normal concentrations of ascorbic acid in both plasma and leukocytes (22,23).
The function of ascorbic acid in collagen synthesis makes the vitamin important in the synthesis of surfactant proteins, which ascorbic acid-dependent hydroxylation for proper folding and stability. The results of five trials have suggested that vitamin C intake may be inversely related to susceptibility to pneumonia. Three controlled trials have found vitamin C supplements effective in preventing pneumonia; two found that treatment effective in reducing the symptoms of that condition (24)
Impaired bone development is a diagnostic feature of juvenile scurvy. This sign is thought to reflect impaired collagen metabolism in the bone matrix. It is not clear, however, whether this function of ascorbic acid may be involved in the apparent value of vitamin C supplements in reducing bone mineral loss in non-deficient adults. This is indicated by the finding of low serum ascorbic acid being associated with markedly (three-fold) increased risk of hip fracture, and of long-term use of vitamin C supplements being positively associated with bone mineral density in women (26,27).
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Key words-Immunity, Common Cold, Infections, Heliobacter pylori, Inflammation, Cardiovascular Health, Stroke, Blood pressure, Heart disease, Exercise, Diabetes, Nerve Function, Pregnancy, Skin health, Wound healing, Cataracts, Lung health, asthma, Bone Health